PROJECT SUMMARY Our long-term objective is to provide a therapy to ameliorate pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD). Current treatment for infants with PH associated with BPD (BPD-PH) is limited to attempts to resolve the underlying respiratory disorder, provide optimal nutrition for lung growth and development, and use of oxygen as a vasodilator. Using this management approach, the survival rates at 6-24 months of age for infants with BPD-PH is only 50-60%. There is evidence that vasodilators other than oxygen may be beneficial for the treatment of these infants. In particular, inhaled nitric oxide (NO) has been shown to function effectively as an acute pulmonary vasodilator in infants with BPD-PH. There is also data showing clinical improvement when inhaled NO is used long term, for 8-90 days. Inhaled NO is expensive and cumbersome expecially when used long-term. An alternate source of NO can be provided with the NO-L- arginine precursor, L-citrulline. Of note, oral L-citrulline has been shown to be bioavailable in adult humans and in the Fike lab newborn piglet model of PH. A safety profile for using oral L-citrulline in neonatal patients with inborn errors of metabolism is already established. Moreover, the Fike lab has shown that treatment with oral L-citrulline ameliorates PH in the newborn piglet model in a dose-dependent fashion. Furthermore, results from studies with the piglet model of PH and from some limited data available from human infants undergoing cardiac bypass surgery, indicate that a circulating plasma L-citrulline trough of 100-150 M in human infants will be needed to ameliorate BPD-PH. The overarching goal of this proposal is to develop oral L-citrulline clinically as a treatment to ameliorate BPD-PH in human infants. Prior to large scale efficacy studies, pharmacokinetic (PK) studies of oral L-citrulline are needed in order to determine the doses and treatment intervals to be used that will achieve target plasma levels of 100-150 M in infants at high risk of developing BPD-PH. The aims of this proposal are to: 1) Characterize the PK profile of oral L-citrulline in infants at high risk of developing BPD-PH in order to define an appropriate dose range (dose and treatment interval) that achieves trough plasma L-citrulline levels of 100-150 M and 2) Evaluate the ability to achieve the target L- citrulline plasma levels in infants at high risk of developing BPD-PH treated for 72 hours with oral L-citrulline. The results of these studies will define the oral L-citrulline dosing strategies to be used in a subsequent large scale efficacy treatment trial for human infants at high risk of developing BPD-PH, an understudied population of patients in desperate need of new therapies.